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f. 3* 




PROGRESS REPORT ON 



A I z h e i 

i s e a s e 
19 9 5 



ff'^^/^'T-f-' 






■ ^ ^ ♦ ^ 

National Institute on A^ing 
National Institutes of Health 




TABLE OF CONTENTS 



ALZHEIMER S DISEASE 

Prevalence and Costs of Alzheimer's Disease 
Research Directions 



STRUCTURE AND FUNCTION 
OF THE BRAIN 



CHANCES IN THE BRAIN 
IN ALZHEIMERS DISEASE 

Amyloid Plaques 

Neurofibrillary Tangles 



ADVANCES IN IDENTIFYING 

RISK FACTORS FOR 

ALZHEIMERS DISEASE 

The Link Between Alzheimer's Disease and ApoE 
Genes in Early-Onset Alzheimer's Disease 
Lower Educational and Occupational Levels 

Associated With Alzheimer's Disease 
Environmental Suspects 



ADVANCES IN DIAGNOSING 

ALZHEIMERS DISEASE 14 

Research on an Eye Test To Diagnose Alzheimer's Disease 

Changes in Immediate Visual Memory 
Predict Cognitive Impairment 

ADVANCES IN TREATING 

AND PREVENTING 

ALZHEIMERS DISEASE 17 

Inverse Association of Anti-Inflammatory 
Drugs and Alzheimer's Disease 

Estrogen 

Research on Dementia Special Care Units 

Alzheimer's Disease Centers Program 

RESEARCH CONDUCTED 

By OTHER NIH INSTITUTES 21 

National Institute of Diabetes and Digestive 

and Kidney Diseases 
National Institute of Neurological Disorders and Stroke 
National Institute of Arthritis and 

Musculoskeletal and Skin Diseases 
National Institute on Deafness and 

Other Communication Disorders 
National Institute of Mental Health 
National Center for Research Resources 
National Eye Institute 
National Institute of Allergy and Infectious Diseases 

OUTLOOK 28 



ALZHEIMER S DISEASE 



ALZHEIMERS DISEASE 



W Izheimers disease (AD) is the most common 
IH cause of dementia, or mental deterioration, 
1 1 among people age 65 and older. A slowly 
rV degenerative brain disease, AD is marked 
J. Jl.by changes m behavior and personality and 
by an irreversible decline m intellectual abilities. It 
impairs thinking, memory, and judgment, advanc- 
ing in stages that range h-om mild forgetfulness to 
severe dementia. The course of the disease varies 
from person to person, as dc^es the rate of decline. 
The average duration of AD is from 4 to 8 years. 

People with this disease may forget how to 
do simple tasks, like brushing their teeth or comb- 
ing their hair. Often, they are unable to think 
clearly or remember the right names of familiar 
objects or people. Eventually, they become com- 
pletely dependent on others for their care. 

Risk for AD increases with advancing age. 
After age 65, the percentage of people who suffer 
from AD or other dementias doubles with every 
decade of life. However, AD is not a part of normal 
aging. AD and other dementing disorders of old 
age are caused by specific diseases. Without disease, 
the human brain continues to function well, often 
into the tenth decade of life. 



Prevalence and Costs of Alzheimer's Disease 

Currently, an estimated 4 million Americans suffer 
from AD. In addition, the lives of countless care- 
givers are affected by this devastating illness. 
Families experience emotional, physical, and finan- 
cial stress. They watch their loved ones become 
increasingly forgetful, agitated, and confused. 
Many caregivers, most of them women, juggle 
child care and jobs while caring at home for 

■ 44* 

/\ recent study cstiiricitca that 
the cost o\ caring lor one person 
with AD is more than $47, OOO 
a year, whether the patient lives 
at home or in a nursing home. 

relatives with AD who cannot function on their 
own. As the disease progresses and the abilities of 
people with AD steadily decline, family members 
face painful decisions about the long-term care of 
their loved ones. 

Moreover, AD puts a heavy economic burden 
on society A recent study estimated that the cost 
of caring for one person with AD is more than 
$47,000 a year, whether the patient lives at home 
or in a nursing home. For a disease that can range 
in duration from 2 to 20 years, the overall costs 
of AD to families and to society are staggering. 

Other factors m our changing society com- 
pound the problem of AD. Life expectancy has 
been increasing since the turn of the last century 



ALZHEIMERS DISEASE 



ALZHEIMERS DISEASE 



During the past three decades, improvements in 
pubhc health measures, diet, and health behavior 
have brought about dramatic demographic 
changes, including a lower birthrate. Thus, today 
in most industrialized countries, the 85+ age group 
is the fastest growing segment of the population. 
The challenge of paying for health care for this 
population has yet to be tackled. 

In light of these issues, AD, which primarily 
affects older people, represents a major health 
concern and expense for the United States. Until 
researchers find a way to cure or prevent AD, the 
number of people living to very old age (85+) and 
at risk for AD will continue to increase dramatically 
Providing and financing the care of a growing 
older population present special challenges for 
our health care system. 

Research Directions 

AD research falls into three broad, overlapping 
areas of emphasis: cause(s)/risk factors, diagnosis, 
and treatment/caregiving. Research into the basic 
neurobiology of aging is critical to understanding 
what goes wrong in the brain affected by AD. 
Understanding the mechanisms by which nerve 
cells lose their ability to communicate with each 
other and the reasons for selective nerve cell death 
is at the heart of the worldwide scientific effort to 
discover the cause, or causes, of AD. 

Epidemiology is an important research tool in 
determining risk factors and identifying potential 
interactions between genetic and non-genetic fac- 
tors. Recent discoveries about the possible roles of 
inherited traits and education as risk factors for AD 
have taken researchers in new directions in their 



search for answers. In addition, researchers are 
looking for better ways to diagnose and treat AD, 
improve a patients ability to function, and support 
the caregivers of people with AD. 

The National Institute on Aging (NIA) has 
primary responsibility for research aimed at 
finding ways to prevent, treat, and cure AD. This 
report highlights recent progress in AD research 
conducted or supported by the NIA and other 
components of the National Institutes of Health 
(NIH), including the: 

• National Institute of Diabetes and 

Digestive and Kidney Diseases 

• National Institute of Neurological 

Disorders and Stroke 

• National Institute of Arthritis and 

Musculoskeletal and Skin Diseases 

• National Institute on Deafness and 

Other Communication Disorders 

• National Institute of Mental Health 

• National Center for Research Resources 

• National Eye Institute 

• National Institute of Allergy and 

Infectious Diseases 
Additional AD research projects, which are not 
summarized in this report, are supported by the: 
National Cancer Institute; National Heart, Lung, 
and Blood Institute; National Institute of Dental 
Research; National Institute of Child Health and 
Human Development; National Institute of 
Environmental Health Sciences; National Institute 
of Nursing Research; National Center for Human 
Genome Research; and Fogarty International Center. 



STRUCTURE AND FUNCTION 
OF THE BRAIN 



STRUCTURE AND FUNCTION 
OF THE BRAIN 



The brain integrates, regulates, and controls 
functions for the whole body, governing cog- 
nition, personality, and the senses. We are 
able to speak, move, and remember because 
of complex chemical processes that take 
place in the brain. The brain also regulates body 
functions that occur without our knowledge or 
direction, such as our heartrate and breathing. 
The human brain is made up of billions of 
nerve cells, called neurons, which communicate 
with one another through a large array of biological 
and chemical signals. Even more numerous are glial 
cells, which surround, support, and nourish neu- 
rons. Each neuron has a cell body, an axon, and 

■ 44* 

Survival or nerve cells in the 
Drain aepends on the proper 
functioning of many interrelated 
systems that normally work in 
harmony. 

dendrites. The nucleus within the cell body controls 
the cells activities. The axon, which extends from 
the cell body, transmits messages to other neurons. 
Dendrites receive messages from axons of other 
nerve cells or from specialized sense organs. 

Communications between neurons and other 
organs are transmitted through the synthesis and 
release of chemicals. When a nerve impulse reaches 
the end of the neuron, the signal triggers the 



release of neurotransmitters. These chemicals carry 
messages from the axons of nerve cells across the 
synapse (the gap between nerve cells) to the den- 
drites of other neurons. In this way, signals can 
travel back and forth across the brain in a fraction 
of a second. Millions of signals flash through the 
brain every moment. 

Groups of neurons in the brain have certain 
jobs. For example, the cerebral cortex is a collec- 
tion of neurons involved in thinking, learning, 
remembering, and planning. 

Survival of nerve cells in the brain depends on 
the proper functioning of many interrelated systems 
that normally work in harmony. These systems 
control nerve cell activity related to communication, 
metabolism, and repair. The first system, communi- 
cation between nerve cells, is described above. 
The loss or absence of any of several chemical mes- 
sengers disrupts cell-to-cell communication and 
interferes with normal brain function. 

The second system, metabolism, refers to the 
process whereby cells and molecules break down 
chemicals and nutrients into energy Efficient 
metabolism in nerve cells depends on blood circu- 
lation to supply the cells with important nutrients, 
such as oxygen and glucose (a sugar). A sustained 
reduction in the supply of these nutrients can lead 
to nerve cell death. 

The third system repairs and cleans up nerve 
cells. Unhke most other body cells, neurons live 
a long time. When neurons die, they cannot grow 
back or be replaced. Instead, living neurons 
constantly remodel themselves. Any disruption in 
cell cleanup and repair can have disastrous conse- 
quences for cell functioning. Research shows that 
the damage seen in AD is associated with changes 
in all three systems: nerve cell communication, 
metabolism, and repair. 



C HANCES IN THE BRAIN 
IN ALZHEIMER S DISEASE 



CHANCES IN THE BRAIN 
IN ALZHEIMER S DISEASE 



In AD, the intricate process of communication 
between nerve cells breaks down. The destruc- 
tive forces involved in AD ultimately cause 
nerve cell dysfunction, loss of connections 
between nerve cells, and death of some nerve 
cells. Death of neurons in key parts of the AD 
brain severely affects memory, cognition, and 
behavior. 

AD destroys neurons in parts of the brain 
involved with cognition, especially the hippocam- 
pus (a structure deep in the brain that plays an 
important role in memory encoding). As the hip- 
pocampal nerve cells degenerate, short-term mem- 
ory falters, and often, the ability to perform 
familiar tasks begins to decline as well. AD also 
attacks the cerebral cortex (the outer layer of the 
brain). The greatest damage occurs in areas of the 
cerebral cortex responsible for functions such as 
language and reasoning. Here, AD begins to take 
away language and change a persons judgment. 
Emotional outbursts and disturbing behaviors, 
such as wandering and agitation, appear with 
increasing frequency as the disease progresses. 

In the final stages, AD wipes out the affected 
persons ability to recognize close family members 
or communicate in any way; the person becomes 



totally dependent on others for care. People with 
AD often live for years, ultimately succumbmg 
to a number of other diseases, but most often 
pneumonia. 

Two abnormal structures are found in the AD 
brain: amyloid plaques and neurofibrillary tangles. 
Located outside and around neurons, plaques con- 
tain dense deposits of an amyloid protein and other 
associated proteins. Neurofibrillary tangles are 
twisted fibers inside neurons. Progress has been 
made in determining the makeup of amyloid 
plaques and neurofibrillary tangles and in propos- 
ing mechanisms that could account for their 
buildup in AD. 

Amyloid Plaques 

In AD, plaques develop in areas of the brain related 
to memory. These plaques consist of beta-amyloid 
mixed with dendritic debris from surrounding cells. 
Beta-amyloid is a protein fragment clipped from a 
larger protein (amyloid precursor protein) during 
metabolism. However, researchers do not know 
whether amyloid plaques cause AD or result from it. 



CHANGES IN THE BRAIN 
IN ALZHEIMER S DISEASE 



C HANCES IN THE BRAIN 
IN ALZHEIMER S DISEASE 



Amyloid precursor protein (APP) is a member 
of a larger gene family of membrane proteins. During 
metabolism, APP pokes through the nerve cell 
membrane (wall), part inside the cell, part outside. 
Pausing there only briefly, it is replaced by new APP 
molecules being produced in the cell. While APP 
is embedded in the membrane, enzymes called 
proteases split APP in two. Only when the splitting 
occurs at a particular spot on APP is beta-amyloid 
the substance that is set free. 

After the splitting, how the beta-amyloid seg- 
ment moves through or around the nerve cells is 
less clear. However, in the final stages of its journey, 
it IS known to join up with other beta-amyloid 
filaments and fragments of dead and dying 
dendrites. Together, these form the dense and 
insoluble plaques that characterize AD. 

Large numbers of beta-amyloid deposits in the 
brain can occur in older humans and some other 
mammals without surrounding nerve cell changes. 
This finding suggests that beta-amyloid initiates 
and/or is only an early disordered product in a 
slow, multi-step process that ultimately leads to 
brain cell malfunction. 



Several studies have centered on how beta- 
amyloid is processed and how APP is broken down 
by enzymes. Other investigations are seeking clues 
in beta-amyloids environment. For example, sub- 
stances near beta-amyloid may bind to it normally 
and thus keep it in solution. But in AD, according 
to one theory, something causes the beta-amyloid 
to drop out of solution and form insoluble plaques. 
Another candidate for the role of keeping beta- 
amyloid in solution is a form of a protein called 
apolipoprotein E (ApoE). 

Other areas of research center on how beta- 
amyloid affects neurons. In one laboratory study, 
hippocampal neurons died when beta-amyloid was 
added to the cell culture, suggesting that the pro- 
tein is toxic to neurons. Results of another recent 
study suggest that beta-amyloid breaks into frag- 
ments, releasing free radicals that attack neurons. 
Free radicals are unstable molecules that can do 
damage in the body. In AD, a buildup of oxygen 
free radicals, leading to the breakdown of nerve 
cell membranes, is thought to play a role in cell 
death. 

The precise mechanism by which beta-amyloid 
may cause nerve cell death is a mystery. However, 
one recent finding suggests that beta-amyloid 
forms small channels in neuron membranes. These 
channels may allow excess amounts of calcium to 
enter the nerve cell, which is a lethal event. 

Other recent studies indicate that beta-amyloid 
disrupts potassium channels, which also could 
affect calcium levels. Yet another study links beta- 
amyloid to reduced choline levels in nerve cells. 



CHANCES IN THE BRAIN 
IN ALZHEIMER S DISEASE 



CHANGES IN THE BRAIN 
IN ALZHEIMER S DISEASE 



Since choline is an essential component of acetyl- 
choline, a neurotransmitter, this finding suggests 
a link between beta-amyloid and acetylcholine. 

Beta-amyloid is not the only protein implicated 
in AD. Not long after the discovery of beta- 
amyloid, scientists found the protein that is the 
principal component of neurofibrillary tangles, the 
other hallmark of AD. 

Neurofibrillary Tangles 

Neurofibrillary tangles are abnormal collections 
of twisted threads found inside nerve cell bodies. 
They are the remains of the neurons microtubules, 
the cells internal support stractures. The chief 
component of tangles is a protein called A68, 
a form of tau. 

In healthy neurons, microtubules are formed 
like train tracks, long parallel rails with cross- 
pieces, that guide nutrients from the bodies of the 
cells down the ends of the axons. In cells affected 
by AD, these structures collapse. Tau normally 
forms the crosspieces of the microtubules, but 
in AD It twists into paired helical filaments, two 
threads wound around each other. These paired 
helical filaments are the major component of 
neurofibrillary tangles. No one has discovered 
yet why the microtubules collapse, but according 
to one theory, it may be due to the presence of 
a gene product called ApoE4. 

The collapse of nerve cell supports may result 
in the breakdown of communication between 
nerve cells and finally cause neurons to die. Still 
unknown, however, is whether abnormal process- 
ing causes tau to come away from the nerve cell 



supports or whether abnormal processing is the 
result of tau being gathered into the paired helical 
filaments. In addition, abnormal tau processing 
may simply indicate problems with metabolism 
of other, as yet unknown, nerve cell proteins. 
Sustained triggering of a single enzyme may 
disrupt other normal body functions that affect 
the survival of brain cells. To determine why some 
nerve cells are vulnerable to AD and others are 
not, researchers first must understand the causes 
of abnormal processing and the regulation of 
certain enzymes. 

■ 4 4 * 

In ncaltny neurons, m i c r o t u d u I e s 
arc I o r m e a like train tracks, 
long parallel rails with cross- 
pieces, that guide nutrients.... 
In cells aiiected by A L) , these 
structures collapse. 

Scientists may be able to develop animal models 
using mice that produce excess enz)Tnes involved 
m tau processing. Further clues may lie in recent 
research using "knockout" mice (mice m which the 
regulation of an enzyme that helps process tau is 
altered). These and other routes could lead to an ani- 
mal model for use m testing drugs to re\'erse or limit 
early brain cell damage caused by AD. 



ADVANCES IN IDENTIPyiNC 
RISK FACTORS FOR ALZHEIMER S 
DISEASE 



ADVANCES IN IDENTIFYING 
RISK FACTORS FOR ALZHEIMER S 
DISEASE 



"tt khough healthy aging does not result m 
II dementia or AD, aging remains the most 
I H strongly associated risk factor for AD. Family 
f"! history is another important risk factor. 
J. S. A history of AD m a parent or sibling 
increases the odds of developing AD by three to 
four times. Researchers believe that genetic (inher- 
ited) factors may be involved in more than half of 
the cases of AD. In addition, a severe head injury 
that leads to a brief loss of consciousness doubles 
the risk of developing AD later in life. These three 
risk factors — age, family history, and head injury — 
meet the accepted epidemiologic criteria for causal 
factors: they provide a plausible biological explana- 
tion, and their effects are strong and consistent. 

Other risk factors that do not meet the above 
criteria have been studied, including exposure to 
environmental toxins (such as aluminum) or to 
chemicals (such as benzene and toluene). The 
detection of aluminum, zinc, and other metals 
m the bram tissue of people with AD is being 
studied to see whether such deposits influence 
the disease process or whether they are the results 
of disrupted bram structures. In addition, gender 
may play a role in the disease. Further research 



is needed to confirm recent data showing higher 
rates of AD among women. This finding may only 
reflect the effects of age, since women live longer, 
on average, than men. 

It is becoming clear that the cause of AD is not 
a single factor, but a host of factors that interact 
differently in different people. In most cases, 
genetic factors alone are not enough to bring on 
AD. Genetic indicators have been found in some 
patients with the disease and in their relatives who 
do not yet show signs of impairment. Other risk 
factors may combine with a persons genetic make- 
up to increase the chances of developing AD. 



4 4 # 



l>. 



1 



that t h 



It IS becoming clear tnat tne cause 
Of AU is not a single 'actor, out 
a host or 'actors that interact 
di'ierently in aiiierent people. 

Researchers stud}dng the incidence and preva- 
lence of AD and related dementias in later life seek 
to identify specific risk factors for AD and to show 
how and why AD develops. Incidence refers to 
the rate at which new cases of a disease occur. 
Prevalence is the percentage of the entire population 
with the disease at a given time. By studying people 
in different ethnic, racial, and social groups, scien- 
tists may discover additional nsk factors for AD. 
These risk factors, in turn, may suggest new theories 
that can be tested regarding the diseases origin. 



ADVANCES IN IDENTIPyiNC 
RISK FACTORS FOR ALZHEIMER S 
DISEASE 



ADVANCES IN IDENTIFyiNC 
RISK FACTORS FOR ALZHEIMER S 
DISEASE 



In the past year, researchers have examined 
risk factors that may speed up or slow down the 
onset of AD and increase or decrease a persons 
risk of AD. They focused on determmmg whether 
ApoE, education and occupation levels, a gene on 
chromosome 14, or zinc, aluminum, and other 
metals are related to AD. Their findings eventually 
may lead to treatment and prevention strategies. 

The Link Between Alzheimer's 
Disease and ApoE 

A gene is the biologic unit of heredity that has a 
precise location on a chromosome. Chromosomes 
are structures in the nucleus of cells that transmit 
hereditary information using a molecule called 
deoxyribonucleic acid (DNA). Genes direct the man- 
ufacture of every enzyme, hormone, growth factor, 
and other protein in the body They help deter- 
mine a persons traits, for example, what he or she 
looks like. Genes are made up of four chemicals, 
or bases, arranged in various patterns within the 
DNA. Each gene has a different sequence of bases, 
and each one directs the manufacture of a different 
protein. Even slight akerations in the DNA code of 
a gene can produce a faulty protein. And a faulty 
protein can lead to cell malfunction and eventually 
disease. 

Genetic research has turned up evidence of 
three gene alterations that are more common in 
AD patients than in the general population. One, 
the ApoE4 gene on chromosome 19, has been 
linked to the most common form of AD, called 
late-onset AD, which appears in older people. 



Researchers also have found genes on chromo- 
somes 14 and 21 that are more common among 
people who develop AD earlier, in middle age. 

Everyone has ApoE, which helps transport 
cholesterol in the blood throughout the body. 
The gene for ApoE occurs m three versions: ApoE2, 
ApoE3, and ApoE4. Every person inherits two 
ApoE genes, one from each parent. Scientists are 
studying people with different versions of this 
gene. ApoE3 is the most common one found m 
the general population. However, ApoE4 occurs m 
about two-thirds of all late-onset AD patients and is 
not limited to people with a family history of AD. 

Collaborating researchers at the Duke University 
General Clinical Research Center and the Joseph 
and Kathleen Bryan Alzheimer's Disease Research 
Center in Durham, North Carolina, studied the 
relationship between ApoE4 and AD. Their research 
was supported by the NIA and the National Center 
for Research Resources (NCRR). These scientists 
found that the risk for AD m people v/ith the gene 
for ApoE4 is three times greater than that for other 
people. For example, a 78-year-old person with 
two copies of the gene for ApoE4 has a 98 percent 
chance of having the disease, with one copy a 
60 percent chance, and with no copies a 25 per- 
cent chance. 



ADVANCES IN iDENTIPyiNC 
RISK FACTORS FOR ALZHEIMER S 
DISEASE 



ADVANCES IN IDENTIFYING 
RISK FACTORS FOR ALZHEIMER S 
DISEASE 



In addition, this research shows that the pres- 
ence of ApoE4 also lowers the age of onset of AD. 
On average, people with two copies of the gene for 
ApoE4 start showing AD symptoms before age 
70 and are eight times more likely to develop 
AD than those who have two copies of the more 
common ApoE3 version. For those with no copies 
of ApoE4, the average age of onset is older than 
85 years. According to these scientists, AD risk 
increased because the age of onset decreased. 
In some unknown way, ApoE4 may speed up 
the AD process. 

These researchers also found that ApoE is 
localized m the senile plaques and neurofibrillary 
tangles found in AD. Moreover, Duke University 
researchers now believe that ApoE is located 
in all neurons m both healthy and AD brains. 

Researchers at the Mayo Clinic in Rochester, 
Minnesota, followed 71 older patients with mild 
memory impairment. Almost half had clinical 
dementia after 3 years. Over two-thirds of those 
with clinical dementia with a copy of the gene 
for ApoE4 continued to decline, and ApoE4 best 
predicted who would decline. ApoE4 appears to 
mark susceptibility to AD. However, the presence 
of ApoE4 in a blood sample does not predict AD. 
A person can have ApoE4 and not get the disease, 
and a person can get AD without having ApoE4. 



The relatively rare protein ApoE2 may protect 
people against the disease; it seems to lower the 
risk for AD and increase the age of onset. For 
instance, people with one ApoE2 gene and one 
ApoE3 gene have only one-fourth the risk of 
developing AD as people with two ApoE3 genes. 

Some researchers supported by the NIA and 
NCRR exploring the function of the protein prod- 
uct of ApoE4 point to beta-amyloid. While the 
ApoE4 protein binds rapidly and tightly to beta- 
amyloid, the ApoE3 protein does not. Normally, 
beta-amyloid is soluble, but when the ApoE4 
protein latches on to it, the amyloid becomes 
insoluble. This may mean that it is more likely 
to be deposited in plaques. Studies of brain tissue 
suggest that ApoE4 increases deposits of beta- 
amyloid and that it directly regulates APR 

Other researchers believe that the presence 
of ApoE in neurons may affect certain cell processes 
and how synapses function. Also, scientists con- 
ducting test tube studies found marked differences 
in the rates at which ApoE3 and ApoE4 bind 
to tau protein and to a similar protein found 
in dendrites. One hypothesis suggests that the 
ApoE4 product allows the microtubule structure 
to come undone in some way, leading to the 
neurofibrillary tangles. 

While still controversial and far from proven, 
the hypotheses surrounding ApoE4 are driving new 
research. One next step is to see how tau and beta- 
amyloid react with ApoE in its several forms in living 



10 



ADVANCES IN IDENTIFyiNC 
RISK FACTORS FOR ALZHEIMERS 
DISEASE 



ADVANCES IN IDENTIFYING 
RISK FACTORS FOR ALZHEIMER S 
DISEASE 



cells. Other experiments will be designed to deter- 
mine the actions and role of ApoE. Once these are 
clear, it should be easier to understand how ApoEs 
function might be affected by drugs. For instance, 
if ApoE2 turns out to be beneficial, then substances 
that mimic its effects might be developed to help 
slow or prevent the progress of AD. 

Theories surrounding ApoE4 are not confined 
to the proteins. Its effect on dendrites intrigues 
some scientists, because of findings that dendrites 
in patients with the ApoE4 gene are shorter, pruned 

■ 4 ^ # 

I he relatively rare protein 
ApoL2 may protect people 
a«ainst the disease; it seems 
to lower the risk lor A L) ana 
increase the age ol onset. 

back apparently by some unknown agent. The 
result may be that, compared to normal dendrites, 
these pruned dendrites cannot form as many 
connections with other nerve cells. Although 
this pruning also can occur m people without 
the ApoE4 gene, it happens 20 to 30 years earlier 
In people with ApoE4. 

In addition, environmental factors may interact 
with genetic factors. Researchers at the Neurological 
Institute in New York City believe that repeated 
head injuries do not increase the risk of developing 
AD without ApoE4. However, when ApoE4 is 
present, these scientists found that repeated head 
injuries increase risk for AD by 10 times. 



With ApoE, scientists have a biological indicator 
for AD for the first time. ApoE can be used to sort 
populations and follow the subgroups with the 
hope of finding other risk factors. Scientists still 
must learn how ApoE and its various genes func- 
tion m the brain and relate to other nsk factors for 
AD. Larger population-based studies are needed to 
clanfy the link between ApoE4 and AD, and to 
confirm the protective effect of ApoE2. Further 
explanation of preliminary findings may lead to 
ways to reduce the effects of ApoE4, develop drugs 
to treat or prevent AD, and ultimately, decrease the 
occurrence of AD. Moreover, some scientists sug- 
gest that testing for the ApoF4 gene someday may 
help m the diagnosis of AD. 

Genes in Early-Onset Alzheimer's Disease 

AD can strike early and often m some families — 
often enough to be singled out as a separate form 
of the disease, called early-onset familial AD (FAD). 
Combing through the DNA of some of these early- 
onset FAD families, researchers at St. Marys 
Hospital Medical School m London, England, 
previously found an abnormality m one gene on 
chromosome 21 that is common to a few of the 
families. And they have mapped another gene, 
which occurs m a much larger portion of early- 
onset families, to a region on chromosome 14. 

The gene on chromosome 2 1 carries the code 
for an abnormal form of APP, the parent protem 
for beta-amyloid. The discovery of this gene sup- 
ports the theory that beta-amyloid plays a central 



11 



ADVANCES IN IDENTIPyiNG 
RISK FACTORS FOR ALZHEIMER S 
DISEASE 



ADVANCES IN IDENTIFyiNC 
RISK FACTORS FOR ALZHEIMER S 
DISEASE 



role in some forms of AD, although it has been 
found only in about 5 percent of early-onset FAD 
families. In addition, the gene on chromosome 21 
is the gene involved m Down syndrome. Down 
syndrome is similar to AD in one respect. People 
with Down syndrome have an extra version of 
chromosome 21, and, as they grow older, usually 
develop plaques and tangles like those found m AD. 
Compared to the chromosome 21 gene, the gene 
on chromosome 14 occurs more often in people 
with FAD. However, so far, no one knows exactly 
what gene it is. The gene has been tracked to a 
specific region on chromosome 14. Scientists at the 
University of Washington m Seattle still are trying 
to find the gene among the 10,000 or so DNA 
bases m this region. 

Lower Educational and Occupational Levels 
Associated With Alzheimer's Disease 

Scientists at Columbia University m New York City 
have established a relationship between increased 
risk for AD and lower educational and occupational 
levels. The researchers found that people with either 
lower educational or occupational levels have at 
least twice the risk for developing AD, compared 
to those who have had 6 to 8 or more years of 
schooling. The risk is three times greater when 
low occupation and low education occur together. 



For 4 years, researchers administered yearly 
neuropsychologic tests to 593 people age 60 and 
older to see if any of them began to show signs 
of dementia. The results were analyzed based on 
educational level (kindergarten through college) 
and occupational level, A low level of education 
was set at 8 years of schooling, and occupational 
levels were based on U.S. Census categories. 
At the study's end, over 25 percent of the 
participants showed some sign of dementia. 

These researchers do not know why low 
occupation and education are linked with AD. They 
believe that higher occupational and educational 
backgrounds may allow people to cope better with 
the effects of AD for a longer time before symptoms 
occur. People with more education may develop a 
protective reserve of brain cells or synapses. Also, 
increased mental capacity may allow these people 
to find additional ways to do daily activities. 
Or, education may be related to another factor, 
such as socioeconomic or nutritional status, 
which may be the reason for increased risk. 

This study adds information about psychosocial 
factors related to AD. Investigators and caregivers 
now have another factor to consider when evaluating 
whether faiUng memory and confusion aie signs of 
AD or some other, possibly treatable, problem. 
If some aspects of life experience can delay the 
onset of AD for even a short time, the overall 
prevalence and costs of the disease will be reduced 
significantly. This also could enhance the quality of 
life for many people. 



12 



ADVANCES IN IDENTIFYING 
RISK FACTORS FOR ALZHEIMER S 
DISEASE 



ADVANCES IN IDENTIFYING 
RISK FACTORS FOR ALZHEIMER S 
DISEASE 



Environmental Suspects 

Certain environmental factors, such as metals and 
poisons carried in foods, may play a role in the 
development of AD. The most studied of these 
factors are aluminum and zinc. Researchers 
continue to study whether some metals are related 
to the development of disease markers such as 
plaques and tangles in brain tissue of AD patients. 
To date, no conclusive evidence links metals such 
as aluminum or zinc to AD. 

One of the most publicized and controversial 
hypotheses in AD research concerns aluminum. 
This aluminum theory goes back to the 1970s, 
when researchers found traces of aluminum in 
the brains of AD patients. Many studies since then 
either have not been able to confirm this finding 
or have produced questionable results. 

Aluminum does turn up m higher-than-normal 
amounts in some, but not all, autopsy studies of 
AD patients. Further doubt about the importance 
of aluminum comes from the possibility that the 
aluminum found in some studies did not all come 
from the bram tissues being studied. Instead, some 
could have come from the special substances used 
in the laboratory to study brain tissue. 

Other studies have shown that groups of people 
exposed to unusually high levels of aluminum have 
no increased risk of AD. Moreover, aluminum in 
cooking utensils does not get into food, and the 
aluminum that does occur naturally in some foods, 
such as potatoes, is not absorbed well by the body 
On the whole, most scientists now believe that 
there is little chance that exposure to aluminum 
causes AD. 



Zinc has been implicated m AD m two ways, 
some reports suggesting that too little zmc is a 
problem, others that too much zmc is at fault. 
Too little zinc was suggested by autopsies that 
found low levels of zmc m the brains of AD 
patients, especially m the hippocampus. There is 
some evidence that zinc deficiency can add to the 
symptoms of AD. 

■ 4 4 ♦ 

lo date, no conclusive evidence 
links metals sucn as aluminum or 
zinc to AD. 

On the other hand, results of a recent study 
suggest that too much zmc might be the problem. 
In this laboratory experiment, zmc caused soluble 
beta-amyloid from cerebrospinal fluid to form 
clumps similar to the plaques of AD. Current 
experiments with zmc are pursuing this finding in 
laboratory tests that more closely mimic conditions 
in the bram. 



13 



ADVANCES IN DIAGNOSING 
ALZHEIMER S DISEASE 



ADVANCES IN DIAGNOSING 
ALZHEIMERS DISEASE 



V" dehnitive diagnosis of AD is based on the 
II presence of plaques and tangles m the bram. 
1 1 Plaques and tangles can be found only by 
1^1 examining brain tissue (a bram biopsy), and 
J. JiLthis procedure usually is done only as part of 
an autopsy 

Currently no definitive test exists to diagnose 
AD. However, a probable diagnosis of AD can be 
made based on the patients medical history, a 
physical examination, and tests of menial ability 
Several other conditions, some of which are treat- 
able, also may cause memory or other cognitive 
deficits and must be ruled out. These include 
thyroid gland problems, drug reactions, depres- 
sion, bram tumors, and dementia caused by blood 
vessel disease m the bram. 

A patient history includes a review of present 
and past medical problems, as well as an examina- 
tion of current ability to carry out daily activities. 
Clinical analyses used to decide whether a person 
has AD or another disease include tests of blood 
and urine samples and an examination of a small 
sample of cerebrospinal fluid. 

Neuropsychological tests are used to evaluate 
a persons mental abilities m many areas, including 
memory, problem solving, attention, calculation, 
and language. Brain imaging also may be used to 
detect abnormalities in the bram. The results of 



all tests and the patients medical history help the 
doctor determine if symptoms are caused by AD 
or by another condition. 

Early and accurate diagnosis of AD has a major 
effect on the progress of research on dementia and 
is of utmost concern to patients and their families. 
Although the early and accurate diagnosis of AD is 
difficult, a reliable diagnosis with 80 to 90 percent 
accuracy (when compared to autopsy findings) 
can be obtained in many specialized centers. 

Improving the diagnosis of AD using various 
procedures would allow patients and their families 
to know what stage of the illness they are dealing 
with and help them plan for the future. It also 

■ ♦ 4 ♦ 

Altnougn early and accurate 
diagnosis or AU is dirticult. a 
reliable diagnosis with S O to 9 O 
percent accuracy Iwncn compared to 
autopsy lindings) can e e obtained 
in many specialized centers. 

would improve the planning and design of drug 
trials, because drugs may work more effectively 
to alter the course of the disease m patients with 
early-stage AD. These methods would help identify 
patients early m the course of the illness when 
they have experienced the smallest degree of nerve 
cell damage and cognitive loss. The earlier and 
more accurate the diagnosis, the greater the gain 
in managing the clinical course of the illness, 
determining its natural history, and providing 
information about its causes and treatment. 



14 



ADVANCES IN DIAGNOSING 
ALZHEIMERS DISEASE 



ADVANCES IN DIAGNOSING 
ALZHEIMER S DISEASE 



The NIA supports research to identify dementia 
indicators; develop tests and methods related to 
differential diagnosis, screemng, etiology (the study 
of the causes of the disease), risk factors, and fam- 
ily history; improve research designs; and refine 
diagnostic criteria. 

One goal of current research is to develop an 
accurate test for AD. The search continues for a 
biological indicator that can identify AD cases very 
early in the course of the disease, when treatment 
still could be effective. Neuropsychologic tests 
are needed that pinpoint the stages of AD. These 
tests would separate people who are m the earliest 
stages of AD from people who have cognitive 
deficits that are related to healthy agmg. Brief 
cognitive screening tools are proUferating. How- 
ever, the relationship of the results of one test to 
another, to careful clinical diagnosis of abnormali- 
ties, and ultimately to brain cell death remains 
unknown. 

Experimental technology for imaging the bram 
continues to develop rapidly. New procedures 
include positron emission tomography (PET), 
single photon emission computed tomography 
(SPECT), magnetic resonance imaging (MRI), 
and magnetic resonance spectroscopy imaging 
(MRSl). MRI provides high-resolution images 
of the brain. MRSI allows observation of various 
metabolites in the brain without the use of radio- 
active tracers. Metabolites are substances that 
are produced when energy is made available 
for cell use. Scientists are working to learn how 
metabolites change with aging and with AD and 
how to relate these changes to cognitive impairment. 
MRSl may offer a way to establish early diagnosis, 
determine prognosis, monitor patients, and evaluate 
treatment efficacy. 



Researchers have yet to understand the relation- 
ship between the results of various bram imaging 
methods and the persons clinical condition. In 
addition, methods used to analyze imaging results 
need to be standardized. In the future, researchers 
hope to put information from imaging techniques 
that evaluate structure and those that analyze func- 
tion together into a unified diagnostic summary 

Research on an Eye Test To 
Diagnose Alzheimer's Disease 

Researchers at the Harvard Medical School m 
Boston, Massachusetts, are working on developing 
a simple eye test for detecting the presence of AD. 
Eventually this test may help diagnose patients with 
AD. Preliminary results suggest that monitoring 
pupil dilation (expansion) after exposure to certain 
eye drops may one day be the basis of an easy, 
accurate way to diagnose AD. 

Data m this study suggest that the pupils of 
healthy people or those with non-AD dementia 
dilated about 5 percent after receiving the eye 
drops. The pupils of people with AD dilated 
23 percent. This test pointed to AD m 18 of 19 
people believed to have AD, Furthermore, pupils 
seemed to be sensitive to the chemical very early 
in the course of the disease, when emerging treat- 
ments are likely to be most effective. This test now 
must be studied in many more people to deter- 
mine whether it holds up m different types of peo- 
ple with different types of AD, and distinguishes 
AD from other neurologic illnesses. 



15 



ADVANCES IN DIAGNOSING 
ALZHEIMERS DISEASE 



ADVANCES IN DIAGNOSING 
ALZHEIMERS DISEASE 



Changes in Immediate Visual Memory 
Predict Cognitive Impairment 

NIA researchers have found that changes occurring 
over 6 years m immediate visual memory perfor- 
mance, assessed by the Benton Visual Retention 
Test (BVRT), predict AD before the onset of cogni- 
tive symptoms. Immediate visual memory refers to 
the ability to remember and name, vvathm seconds, 
things seen. The BVRT requires subjects to repro- 
duce geometric designs from memory after studying 
them for 10 seconds. Each test consists of 
10 separate designs with 1 or more figures, and 
the score is the total number of errors made in 
reproducing the designs. 

Researchers m the NIAs Baltimore Longi- 
tudinal Study of Agmg examined data for 254 men 
and 117 women, who were administered cognitive, 
neuropsychologic, and neurologic tests between 
1986 and 1992. These people were generally 
healthy and ranged m age from 55 to 95 at the 
initial testing. Six of them had probable AD, and 
one had definite AD. 



Compared to those without AD, subjects with 
the disease had larger changes m the numbers of 
errors m immediate memory performance over 
the 6 years prior to the onset of AD. This finding 
implies that AD may be identified by changes in 
memory performance sooner than other changes 
can be detected by clinical evaluation. Six-year 
change m immediate visual memory performance 
also predicted cognitive performance from 6 to 
15 years and from 16 to 22 years later. This was 
true even after adjusting for the influences of age, 
general ability, and initial immediate memory. 

In addition, these results suggest that change 
m recent memory performance, a critical compo- 
nent m diagnosing AD, may be an important 
precursor of the development of the disease. Recent 
memory performance generally refers to recall after 
a short delay, such as 20 minutes. 

The results show the value of longitudinal 
studies because predictions of risk for subsequent 
disease are possible only when baseline and 
followup data are gathered before the onset of 
disease. This is particularly important for AD, 
because little is known about the earliest stages 
of AD. However, this period is likely to be when 
the disease is most responsive to treatment. 



16 



ADVANCES IN TREATING 
AND PREVENTING 
ALZHEIMER S DISEASE 



ADVANC ES IN TREATING 
AND PREVENTING 
ALZHEIMERS DISEASE 



There currently is no effective way to treat 
or prevent AD, However, several substances 
are being tested to see if they can slow or 
reverse the decline in those behavioral and 
cognitive skills that are impaired by AD. 
Pharmacologic and behavioral treatments for the 
non-cognitive behavioral symptoms related to AD 
also are being studied. These symptoms include 
aggression, agitation, wandering, depression, 
sleep disturbances, and delusions. 

The drug tacrine (also known as THA or 
Cognex) may temporarily slow the rate of decline 
in memory and thinking ability in some patients 
who are m the mild and moderate stages of the 
disease. Experimental drug treatments may be 
available to AD patients through clinical trials con- 
ducted at large teaching hospitals and universities. 
Several of these experimental drugs have shown 
promise in easing symptoms in some patients. 

Moreover, medications may help control behav- 
ioral symptoms, thereby making some patients more 
comfortable and making their care easier for care- 
givers. For example, several drugs now in use may 
improve sleep patterns, reduce agitation and wan- 
dering, or ease anxiety and depression. 

Scientists studying drug and non-drug treat- 
ments seek to reduce disruptive behaviors, allow 
patients to live in the least restrictive manner 
possible while maximizing their dignity and 
independence, reduce caregiver stress, and 
keep or re-establish patients' self-care abilities. 
In addition, effective treatments would decrease 
significantly the economic costs to families and 
society by reducing the need to institutionalize 



patients. Overall, these research efforts are designed 
to increase the intellectual, emotional, and social 
well-being of patients, families, and caregivers. 

In 1994, the NIA funded a 5-year study to 
screen for potential toxic effects of new drugs to 
treat AD. The data gathered will be used to file 
Investigational New Drug requests with the Food 
and Drug Administration so that compounds can 
be taken quickly from animal testing into human 
clinical trials. 

Thirty-five sites m the Alzheimer's Disease 
Cooperative Study Unit (ADCSU) are located pri- 
marily at the Alzheimer's Disease Research Centers 
and Alzheimer's Disease Core Centers. The ADCSU 
is conducting trials of deprenyl and vitamin E, 
drugs used to treat agitation, an anti-mfiammatory 
agent, and estrogen. In addition, the ADCSU is 
testing neuropsychologic instruments m the areas 
of cognitive change, behavioral change, global 
assessment, and activities of daily living. The 
ADCSU also is adapting instruments for use 
with people who are severely impaired and with 
those who do not speak English. Future ADCSU 
work will involve designing trials to evaluate 
whether a substance can prevent AD. 

In addition, postmenopausal estrogen replace- 
ment therapy, long-term use of anti-mfiammatory 
drugs, and cigarette smoking have been implicated 
as having a protective effect against AD. These 
all need to be confirmed by further and more 
careful studies. 



17 



ADVANCES IN TREATING 
AND PREVENTING 
ALZHEIMER S DISEASE 



ADVANCES IN TREATING 
AND PREVENTING 
ALZHEIMER S DISEASE 



Inverse Association of Anti-Inflammatory 
Drugs and Alzheimer's Disease 

Anti-mflammatory drugs are used to ease symptoms 
of arthritis or related conditions. Recently, they 
have been proposed as a means of slowing the 
progression of AD symptoms. Studies of twins sug- 
gest that the use of anti-inflammatory agents may 
relate to the etiology and prevention of AD. 

NIA- funded researchers at the Duke University 
Medical Center and Johns Hopkins University 
School of Hygiene and Public Health studied 
50 sets of older twins with AD. They found a 
lower incidence of AD among those who had used 
anti-inflammatory drugs to treat arthritis. These 
findings suggest that inflammatory mechanisms 
may be involved in the development of AD. They 
also indicate that anti-mflammatory agents may 
prevent or delay the onset of AD symptoms. 

Estrogen 

Preliminary data from previous animal and human 
studies suggest that estrogen may protect older 
women against AD. However, recent research has 
generated some conflicting results. Initial results 
from one study by researchers at the University 
of Washington, Seattle, provide no evidence that 
post-menopausal estrogen replacement therapy 
influenced the risk of AD m women. Using 
computerized pharmacy data, these researchers 
compared the use of estrogen replacement therapy 



by 107 women with AD and 120 women without 
AD. Estrogen use was not associated with AD. 

Other NlA-funded researchers at the University 
of Southern California School of Medicine, Los 
Angeles, analyzed data for 138 older women who 
had died and whose death certificates listed AD 
or related dementias. Their results suggest that risk 
of AD and related dementia was lower m estrogen 
users than m non-users. Risk of AD decreased 
significantly with increasing estrogen dose and 
with increasing duration of estrogen use. Risk of 
AD also was associated with variables related to 
estrogen levels produced naturally in women. 
Data also suggest that risk of AD increased with 
increasing age at the onset of menstruation and 
decreased with increasing weight. 

Overall, this study suggests that the increased 
incidence of AD in older women who have under- 
gone menopause may be due to estrogen deficiency 
Further research is needed to determine whether 
estrogen replacement therapy can slow down AD- 
related nerve cell death, and delay the onset of AD 
or prevent it altogether. Additional research will 
allow scientists to analyze how and why these and 
other studies have conflicting results. 

Research on Dementia Special Care Units 

Another line of AD research sponsored by the 
NIA concerns the effectiveness of special care units 
(SCU's) across the Nation. The results of these 
studies may provide ways to improve care for 
patients with AD and related dementias. 

Dementia SCU s are long-term care settings 
designed to meet the needs of people with AD 
and related mental impairments. SCU s emerged 



18 



ADVANCES IN TREATING 
AND PREVENTING 
ALZHEIMERS DISEASE 



ADVANCES IN TREATING 
AND PREVENTING 
ALZHEIMERS DISEASE 



in the 1980's as a care option for patients with 
AD. Forces creating a demand for specialized care 
include the growing numbers of older people; the 
recognition that the care needs of people with 
dementia differ from those of physically frail 
people; and the widespread concern that standard 
nursing home care has been unresponsive to the 
special needs of people with AD and related disor- 
ders, their families, and caregivers. 

■ 4- 4 ♦ 

...o\ tne iNation s 15,555 liccnsca 
nursing nomcs, 9-6 percent naa 
aementia Special ^are Units, 
with an estimated capacity o\ 
about 47,878 resiaents. 

Since their beginnings, SCU's have proliferated 
rapidly and grown in diversity. The 1990-91 
National Survey of Special Care Units in Nursing 
Homes found that of the Nations 15,555 licensed 
nursing homes, 9.6 percent (1,497 nursing homes) 
had SCU's, with an estimated capacity of about 
47,878 residents. While most nursing homes with 
SCUs presented some features considered impor- 
tant for SCU's, only 647 met all of them. Pro- 
jections from this survey suggest that 16.7 percent 
of all nursing homes will offer SCU's in 1995. 

To explore the effectiveness of SCU's, the NIA 
funded a 5-year multi-center Special Care Unit 
Initiative, beginning in 1991. Under this program, 
the NIA financed 10 research projects to examine 
SCU's throughout the United States. 



Several research issues have emerged since 
1991. There is a lack of standardization about 
what constitutes an SCU versus a non-SCU. 
Use of uniform descriptive data is critical because 
SCU's vary in size, age of patients, and whether 
or not patients are segregated from the general 
nursing home population. SCU's also can differ 
in how they recruit residents for participation 
in studies. Research studies need to establish 
the diagnosis and cognitive level of residents 
to identify a sample group for study 

The proliferation of SCU's means that for the 
first time in the United States, administrators and 
staff members m numerous nursing homes are 
developing methods of care specifically for their 
residents with dementia. Better methods of care 
cannot be realized without formal research to 
describe, compare, and evaluate the various methods 
being used. There still is a need for more research 
on classification, design characteristics, costs, and 
effectiveness of SCU's. For public policy purposes, 
the most important research questions pertain to 
the effectiveness of SCU's tor their residents, the 
residents' families, and the unit staff members; and 
the impact ot SCU's on residents with and without 
dementia in non-specialized nursing home units. 

Further research will provide a better idea of 
what constitutes "special care" and identify which 
features ol SCU's are most important m terms of 
environment, staffing, activities, care planning, 
admission policies, size, and patient segregation. 



19 



ADVANCES IN TREATING 
AND PREVENTING 
ALZHEIMER S DISEASE 



ADVANCES IN TREATING 
AND PREVENTING 
ALZHEIMERS DISEASE 



Additional studies will determine whether effective 
SCU's cost more than traditional nursing home 
units. Eventually, the results of these studies will 
enable caregivers and health care insurers to 
compare options when shopping for long-term 
care faciUties. 

Alzheimer's Disease Centers Program 

The NIA funds 28 Alzheimer's Disease Centers 
(ADC's) at major medical institutions across the 
Nation. The centers conduct a wide range of 
research, including studies on the causes of AD 
and investigations aimed at diagnosing, treating, 
and managing the symptoms of the disease. 
The ADC Program promotes research, training 
and education; technology sharing; and multi- 
center and cooperative studies of diagnosis and 
treatment. Each ADC has administrative, clinical, 
neuropathology, and education and information- 
sharing cores, or sections. Some ADC's include 
additional cores, such as neuroimagmg and 
data analysis. 

■ 4^ ^ # 

A/l ucn o\ tnc success o\ AD 
research in this country during 
the last \ O years can be attri- 
buted to resources provided at 
the Alzheimer s Disease C^enters. 



Fifteen comprehensive ADC's have fully-fund- 
ed basic, clinical, and behavioral research projects. 
Areas of study range from the basic mechanisms 
of AD to managing the symptoms and helping 
families cope with the effects of the disease. The 
other 13 ADC's are Alzheimer's Disease Core 
Centers, which provide resources to AD 
researchers. 

A program was initiated m 1990 to add satellite 
clinics linked to the ADC's. Currently, 27 satellite 
clinics at 21 ADC's offer diagnostic and treatment 
services and collect research data in underserved, 
rural, and mmonty communities. These programs 
allow members of culturally and ethnically diverse 
communities to take part in research and clinical 
drug trials associated with parent ADC's. 

Much of the success of AD research in this 
country during the last 10 years can be attributed 
to resources pro\aded at the ADC's, including the 
recent discovery of the importance of chromosome 
14 m FAD and the identification of inherited risk 
factors related to ApoE. The ADC's enhance AD 
research by providing a network for sharing new 
ideas as well as research results. 

Other initiatives funded by the NIA depend on 
the ADC's, including regular research grants, the 
Consortium to Establish a Registry for Alzheimer's 
Disease, and the ADCSU. The ADC's proxide 
resources for these efforts, such as patient data, brain 
and other tissue samples, and molecular probes. 



20 



RESEARC H CONDUCTED 
By OTHER NIH INSTITUTES 



RESEARCH CONDUCTED 
By OTHER NIH INSTITUTES 



National Institute of Diabetes 
and Digestive and Kidney Diseases 

National Institute of Diabetes and Digestive and 
Kidney Diseases (NIDDK) research that relates to 
AD generally falls within two areas. The first focuses 
on mechanisms involved in abnormal metabolic 
processes. The second concerns the molecular and 
biochemical mechanisms of cells, including the roles 
of neurotransmitters and ion channels. 

This year, NIDDK grantees reported progress 
m understanding the metabolic processes leading 
to the formation of abnormal amyloid protein, 
a major component of plaques m the brain. 
Although the ultimate cause of neuronal cell death 
remains undetermined, some evidence suggests 
that the buildup of abnormal amyloid protein may 
be involved m this process. 

One goal of NIDDK-supported research is to 
understand the biochemical mechanisms underlying 
amyloid diseases. Researchers are learning how 
APP, a normally soluble protein, is transformed 
into the insoluble fibers that build up m AD 
plaques. This work focuses on a form of abnormal 
amyloid protein that has been implicated m amy- 
loid polyneuropathy, a neurologic disease. This 
form of abnormal amyloid protein is similar but 
not identical to the form found m AD. These 
researchers identified a gene mutation that alters 
an intermediate step in the formation of amyloid 
and appears to be related to abnormal amyloid 
protein production. The findings suggest 
that certain gene mutations may have metabolic 
effects that determine the development of 
amyloid disease. 



National Institute of Neurological 
Disorders and Stroke 

The National Institute of Neurological Disorders 
and Stroke (NINDS) is the principal source of sup- 
port lor neurological research in the United States 
and a major participant m the study of AD. Basic 
studies are aimed at determining the underlying 
causes of AD with the ultimate goal of prevention. 
Clinical research seeks to improve the diagnosis 
and treatment of patients. 

Scientists at the NINDS and NIA have discov- 
ered that adding beta-amyloid to normal skm cells 
causes them to undergo the same type of failure at 
the molecular level previously shown m skin cells 
of patients with AD. By placing a solution with low 
levels of beta-amyloid m culture with normal 
human skm cells, the scientists produced changes 
in potassium channel function similar to those seen 
in skin cells from AD patients. Beta-amyloid is the 
main component of plaques found in bram tissue 
in AD. This finding suggests that beta-amyloid may 
cause the abnormal process that leads to memory 
loss even before it congeals into plaques. This 
research may lead to alternative explanations of 
the causes of memory loss, one of the earliest and 
most common symptoms of the disease. 



21 



RESEARC H CONDUCTED 
By OTHER NIH INSTITUTES 



RESEARC H CONDUCTED 
By OTHER NIH INSTITUTES 



Last year, researchers m the same laboratory 
showed that skin cells from people with AD have 
defects that interfere with the cell's ability to regu- 
late Its concentrations of potassium and calcium 
ions. The flow of potassium and consequent 
uptake of calcium are especially critical in bram 
cells responsible for memory formation and infor- 
mation storage. 

Recently, after treating one group of the skin 
cells with soluble beta-amyloid for 48 hours, scien- 
tists tound that a specific potassium channel was 
absent m all but one of the cells. However, a func- 
tional potassium channel was present in 
94 percent of untreated cells. Results of further 
testing suggest that beta-amyloid selectively targets 
this specific potassium channel, which had been 
absent m skm cells of AD patients. 

These researchers now are working to see 
if similar potassium channel dysfunction occurs 
in central nervous system neurons. The scientists 
have discovered similar defects m nerve cells of 
the olfactory system (related to the sense of smell), 
suggesting that such defects may be present in 
bram cells. 



National Institute of Arthritis 

and Musculoskeletal and Skin Diseases 

Researchers at the National Institute of Arthritis 
and Musculoskeletal and Skin Diseases have made 
strides m finding a treatment for amyloidosis 
(a buildup of amyloid protein m various body 
tissues). This research may lead to a possible treat- 
ment for AD, because a major feature of AD is 
bram deposits of amyloid or amyloid-like material. 

Some forms of amyloidosis are inherited. 
One of these forms, familial amyloid polyneuro- 
pathy (FAP), IS caused by a mutation of the 
transthyretin (T TR) protein. Scientists have devel- 
oped a method for separating normal and mutant 
TTR in bodily fluids, allowing rapid screening and 
diagnosis. This method also allows the ratio of 
normal to mutant TTR to be measured over time. 

These researchers also have reported on liver 
transplants m patients with FAR Almost all normal 
and abnormal TTR is produced in the liver. Patients 
undergoing liver transplants for advanced disease 
showed important improvements m their conditions. 
The amount of mutant TTR present after the 
transplant was reduced markedly. After surgery, 
patients had only normal TTR. This is the first 
successful therapy m patients with FAR 

National Institute on Deafness and 
Other Communication Disorders 

The National Institute on Deafness and Other 
Communication Disorders (NIDCD) studies the 
normal and disordered processes of balance, 
smell, taste, voice, speech, hearing, and language. 
The NIDCD's chemosensory (smell and taste) 
research program includes studies of the olfactor)^ 
receptor cell (a nerve cell in the part of the nose 



22 



RESEARCH CONDUCTED 
By OTHER NIH INSTITUTES 



RESEARCH CONDUCTED 
By OTHER NIH INSTITUTES 



that senses smell). Normally, these nerve cells are 
replaced continually in the body An important 
aspect of this research is the potential for developing 
new strategies to treat nerve cell loss caused by 
aging, injury, and diseases, such as AD. 

Scientists supported by the NIDCD recently 
examined the development of human olfactory 
neurons transplanted into the brains of animals. 
They studied the interaction of these transplanted 
neurons with other brain cells. The transplanted 
neurons not only survived, but developed and 
grew nerve fibers that entered and mingled with 
the animal's other nerve cells. The fact that donor 
olfactory neurons developed and integrated with 
other nerve cells means that the possibility exists 
of forming new neuronal connections. 

The capacity of transplanted olfactory neurons 
to produce new nerve cells is of wide interest not 
only with respect to chemosensory function, but also 
as a model for studying neuron replacement. Further 
research on transplanted neurons may show that 
biological repair of nerve damage from neuro- 
degenerative diseases, including AD, is possible. 

National Institute of Mental Health 

National Institute of Mental Health (NIMH) research 
on AD spans from the genetics and molecular 
biology of the disease to the psychosocial stresses 
faced by family members. 

The NIMH Diagnostic Centers for Psychiatric 
Linkage Studies of Alzheimer's Disease identify 
siblings with and without AD for ongoing studies. 
The centers' goal is to establish a national resource 
of cell lines and clinical data from people with AD 
and their key relatives. 



Advances in the molecular genetic study of 
AD may show how the disorder develops and offer 
ways to identify those at risk for the purposes of 
early intervention. Neurofibrillary tangles found 
in the AD brain largely consist of abnormal forms 
of the cellular protein tau. In the normal bram, 
tau binds to microtubules that provide structural 
support for cells, including neurons. In AD, tau 
takes the form of twisted fibers and does not bind 
to microtubules. 

Using techniques from molecular genetics, 
NIMH researchers have identified tissue at risk 
for AD and other neurodegenerative processes. 
They also have developed a new probe, an anti- 
body that identifies and interacts exclusively 
with neurons that are vulnerable to the disease. 
Antibodies are immune system molecules. 
Antigens stimulate the production of antibodies. 
Each antibody has a unique amino acid sequence 
that allows it to interact with only a certain 
antigen. The above antibody probe stains for 
a different antigen than expected. This finding 
suggests that a host of unknown pathologic 
indicators or gene products may occur in AD. 



23 



RESEARCH CONDUCTED 
By OTHER NIH INSTITUTES 



RESEARCH CONDUCTED 
By OTHER NIH INSTITUTES 



In test tube studies, NIMH scientists have been 
able to grow neuroblasts (immature nerve cells), 
which were taken from inside the noses of AD 
patients and healthy people. They have found 
that AD neuroblasts have increased levels of APP 
fragments. These fragments are thought to include 
the toxic protein beta-amyloid. The amount of 
fragments decreases when theophylline is added 
to the cells, suggesting toxicity and a potential 
therapeutic intervention. 

Recent advances m basic neuroscience research 
link bram structures and functions involved in AD 
and help explain some AD symptoms. Using ani- 
mal models, NlMH-supported researchers have 
found a connection between two areas of the 
bram, one of which allows people to forget an 
emotion-linked memory that no longer is useful. 
When this part of the brain is damaged, it may 
fail to erase an emotional memory or prevent an 
emotional response. This research may bear on 
AD patients' inappropriate emotional responses 
or inability to remember emotionally significant 
information. 

NIMH researchers strive to reduce problematic 
symptoms of AD and help families care for these 
patients. They are studying the relationship between 
disturbed sleep, altered sleep-wake cycles, episodes 



of stopped breathing, daytime sleepiness, and sun- 
downing (or nighttime confusion). By doing so, 
NIMH-funded researchers hope to decrease sleep 
problems and confusion and reduce some disability 
in AD patients. Preliminary studies of patients with 
dementia and normal breathing during sleep show 
they have less confusion in the morning or the 
same amount of confusion as during the previous 
night. This finding suggests that increased confu- 
sion related to a decrease in the amount of oxygen 
breathed in during sleep may represent an early 
phase of sundowning. Studies also are being done 
of the clinical efficacy of several medications 
commonly used for sundowning. 

An NIMH-supported program for caregiving 
spouses of AD patients delayed nursing home 
placements up to 6 months. This program offered 
individual and family counseling and a caregiver 
support group. Compared to other caregivers not 
in the program, the supported spouses showed less 
decline in their own mental and physical health, 
and derived more satisfaction from their social sup- 
port networks. Results suggest that psychosocial 
interventions may relieve some burdens of long- 
term caregiving for chronically impaired older 
adults. This relief may translate into major cost 
reductions for health care delivery systems. These 
findings are important, given the high cost of 
nursing home care and the increasing number 
of people with AD. 



24 



RESEARCH CONDUCTED 
By OTHER NIH INSTITUTES 



RESEARCH CONDUCTED 
By OTHER NIH INSTITUTES 



NIMH-funded research indicates that caregiv- 
ing stress negatively affects the caregivers mental 
health (increased depression), immune system 
function, and physical health. These studies show 
that AD caregivers perform lower on measures of 
their bodies' ability to fight diseases and have more 
infectious disease episodes than do non-caregivers. 
Older, caregiving spouses' immune functions fail 
to return to the level found in controls over a sus- 
tained period. Caregivers also show a lower anti- 
body buildup in response to influenza vaccination. 

■ 44* 

An IN I A/l H -s u ppor tc a program 'or 
caregiving spouses o\ /\ \j patients 
aelayed nursing home placements up 
to 6 montns. I his program oirered 
individual and tamily counseling 
and a caregiver support group. 

Male caregivers may be at risk for the cardio- 
vascular effects of caregiving stresses. Higher levels 
of triglycerides ("bad" cholesterol) and lower levels 
of high-density lipoproteins ("good" cholesterol) 
have been found among male caregivers. Male 
caregivers also have higher levels of: anger, coronary- 
prone behavior, and use of avoidance when coping. 
These results provide the foundation for more 
targeted interventions with caregivers who can 
be identified as more or less at risk for mental 
health and physical health problems. 



Although most older Americans lead healthy 
lives unaffected by significant mental disorder, 
up to 12 percent of people age 65 and older 
experience an anxiety disorder, depression, or 
some form of dementia. Mental disorders m late 
life are not an outcome of normal aging. Instead, 
they are illnesses that result in significant disability, 
dependency, and early death. Sleep problems can 
lead to inappropriate use of sleeping pills, fatigue, 
and disorientation, which in turn reduce quality 
of life and increase the chances of illness. Of the 
5 percent of older Americans in nursing homes, up 
to one-fifth suffer from some form of unnecessary 
depression, which increases the risk of mortality 

Mental disorders in older people often occur 
along with physical illness and pam symptoms. 
Older people are less likely to seek mental health 
services, and many seek assistance from primary 
care physicians when faced with mental illness. 
Unfortunately, mental disorders in older people 
typically go undetected, and many do not receive 
available treatments. This is particularly tragic 
for depressed older people who commit suicide. 
More than 70 percent of older men (the highest 
risk group for suicide in this country) visit their 
primary care physicians within 1 month before 
committing suicide. 



25 



RESEARCH CONDUCTED 
By OTHER NIH INSTITUTES 



RESEARCH CONDUCTED 
By OTHER NIH INSTITUTES 



Safe and effective treatments are available for 
depression, anxiety, and sleep disorders. Efforts 
to refine treatments include studies of how people 
metabolize psychotropic medications (drugs that act 
on the mind) with and without other medications 
for physical disorders. Research on psychosocial 
treatments alone and in combination with medica- 
tions over long periods are providing important 
data for recommended treatment practices. Like 
other diseases, it appears that many mental disorders 
require long-term treatments. 

National Center for Research Resources 

Through its national network of clinical, animal, 
and other research resource centers, the National 
Center for Research Resources (NCRR) supports 
studies to advance understanding and treatment of 
AD and other disorders affecting older Americans. 

In addition to research at Duke University 
on ApoE (see pages 9-10), the NCRR supports 
several potential therapies for AD at Regional 
Primate Research Centers (RPRC's). Researchers 
at the University of Washington RPRC have used 
a compound (leupeptin) that accelerates brain 
aging in rats to stimulate an effect similar to AD 
in aged monkeys. 



At the California RPRC, scientists found that 
age-related neuron weakening in part of the brain 
can be prevented by adding nerve growth factor 
(NGF) in primates. An NGF is a protein that fos- 
ters development of nerve cells and may protect 
certain nerve cells from damage. It supports cells 
that produce the vital neurotransmitter, acetyl- 
choline. Other neurotrophic factors (components 
that help maintain body tissues and are regulated 
by nervous functions) also may be useful in therapy 
for this degeneration. Using gene therapy tech- 
niques, researchers have found that NGF-produc- 
ing fibroblasts (cells that are part of the tissue that 
binds together and supports the various body 
structures) survive up to 6 months in the adult 
primate brain. 

At the Wisconsin RPRC, scientists are mapping 
the distribution of neurotrophins and their recep- 
tors. This work will help identify growth factors 
that may allow rescue of neurons in brain regions 
affected by AD. 

National Eye Institute 

The National Eye Institute continues to support a 
study of human binocular vision and motion per- 
ception. Binocular vision is the merging of images 
from both eyes into a single image perceived by 
the visual cortex of the brain. Motion perception 
is the ability to perceive clearly the direction and 
speed of a moving object. This research focuses on 
interactions among the neurological mechanisms 
underlying these aspects of vision and stereopsis. 
Stereopsis is the ability to combine the images 



26 



RESEARCH CONDUCTED 
By OTHER NIH INSTITUTES 



RESEARCH CONDUCTED 
By OTHER NIH INSTITUTES 



of two pictures of an object seen from slightly 
different viewpoints. It refers to how people see 
something as both a solid and three-dimensional 
object. These study areas may provide important 
clues about the perceptual consequences of neuro- 
logic dysfunctions in AD. Specific areas under 
study are: the coexistence of stereopsis and bino- 
cular competition; the regions in the brain associ- 
ated vvdth binocular suppression (relative to 
the analysis of motion information) and visual 
attention; interactions between stereopsis and 
depth perception in specifying structure from 
motion; and motion perception and stereopsis 
in AD patients. 

National Institute of Allergy 
and Infectious Diseases 

Studies conducted by the National Institute of 
Allergy and Infectious Diseases (NIAID) with the 
greatest relevance to aging and AD involve research 
to develop a drug to prevent scrapie. Scrapie is an 
infectious, neurodegenerative disease of sheep and 
goats. Scrapie is similar to AD in that accumulations 
of abnormal protein form amyloid plaques in the 
brain. One advantage of scrapie research is that, 
unlike AD research, animal and cell culture models 
already exist in which to study amyloid formation 
and therapeutic strategies. Current NIAID research 
on scrapie offers potential for understanding the 
clinical development of AD. 

The agent that causes scrapie is an unusual 
infectious particle that contains no nucleic acid 
and consists of a single protein, called PrP-res. 



NIAID scientists found that when a normal protein 
typically found in the brain (PrP-sen) interacts 
with an altered form of itself, the altered form is 
converted to PrP-res. When PrP-res builds up m 
the brain, amyloid plaques form. Although the 
major proteins forming plaques differ m scrapie 
and AD, an understanding of how amyloid is 
formed in scrapie may provide insights about 
plaque formation m the AD brain. 

NIAID intramural scientists have found that 
Congo red, a chemical dye, can delay the onset 
of scrapie m mice by preventing the buildup of 
PrP-res m the bram infected with scrapie. The fact 
that Congo red shows some efficacy m preventing 
the development of scrapie m laboratory animals 
suggests that a similar substance might be useful 
in preventing the development of AD m humans. 

NIAID scientists also are conducting test tube 
studies related to agmg. Using a new technique, 
NIAID researchers have isolated almost all classes 
of stem cells (the earliest developmental form of 
blood cells) from mouse bone marrow. This isolation 
process does not appear to alter the cells' normal 
behavior, suggesting that stem cells are reliable 
for studying normal blood cell development. 
Isolated stem cells now can be used to evaluate 
the effects of the agmg process on blood cell 
development. 



27 



OUTLOOK 



Scientists have learned a great deal about 
AD in the past year. Projects m 1995 will 
seek to identify the gene on chromosome 
14 responsible for one form of early-onset 
AD and to understand better how ApoE 
works as a risk factor for AD. More specifically, 
researchers are interested in learning how ApoE 
relates to plaques and tangles. Scientists also will 
look for ways to enhance the use of imaging tech- 
niques, especially MRI, as early diagnostic or pre- 
dictive tools for AD. Improved MRI technology is 
expected to allow researchers to identify initial 
changes in the hippocampus in AD. PET scans 
eventually may detect changes m bram metabolism 
that precede AD onset by as much as 20 years. 
PET scans also may monitor possible drug thera- 
pies that could prevent the severe nerve damage 
and memory loss that occur m AD patients. 
Clinical studies of estrogen and anti-inflammatory 
agents will build on evidence gained from previous 
epidemiologic studies. Another important area of 
research in the next few years will focus on 
behavioral interventions for patients and training 
programs for caregivers. Taken together, these 
avenues of research will help scientists to under- 
stand the causes of AD, to diagnose the disease 
earlier, and to improve treatment and caregivmg 
strategies. 

■ 4 4 # 



28 





RC523 N213 P94 

PROGRESS REPORT ON ALZHEIMER'S 

DISEASE 1995 




■IKHI mOBBBBBlB^HBH^ WM^MMlllMyilllllll illl SBH 








>r additional copies of this report or further 
formation about Alzheimer's disease, please contact: 



Alzheimer's Disease Education and Referral Center 

RO. Box 8250 

Silver Spring, Maryland 20907-8250 



800-438-4380